The overall purpose of this proposal is to further understanding of the neural and behavioral mechanisms involved in the inheritance of a predisposition towards alcoholism. Additionally, this proposal seeks to identify neural and behavioral effects of previous alcohol experience that might interact with a predisposition towards high alcohol consumption. This proposal will train the principle investigator to use neurochemical and neuropharmacological techniques. To study differences in alcohol- related traits, this work will use High- and Low- Alcohol Preferring (HAP and LAP) mice which, along with their replicate and control lines, greatly differ in free-choice alcohol consumption as a result of selective breeding. One aim of the proposal is to determine whether these mice-show innate differences in neurochemistry: previous findings have indicated that humans and animals that show high alcohol consumption may be deficient in serotonergic and/or dopaminergic function. To that end, analysis of tissue levels of monoamines and their metabolites, and quantitative autoradiography for selected monoamine-related receptors and transporters will be used. Studies will also determine whether these mice differ in intravenous self-administration of alcohol. This procedure is a measure of alcohol's rewarding effects that is not influenced by any potential genetic differences in sensitivity to the taste of alcohol; our expectation is that HAP mice will be more likely to self-administer alcohol intravenously. Preliminary data indicating that HAP but not LAP mice show locomotor sensitization to alcohol allows testing of the hypothesis that sensitization to the locomotor-activating effects of alcohol is correlated with changes in neurochemistry and reward. To determine whether HAPs differ from LAPs in how alcohol experience affects alcohol sensitivity, two kinds of experiments will be done: ones in which both HAP, and LAP mice receive equal amounts of alcohol, and ones in which HAP mice freely consume alcohol. Studies will assess effects of alcohol experience on monoaminergic neurochemistry and on the rewarding effects of alcohol, as measured by conditioned place preference, in both lines. Our hypothesis, based on the locomotor activity data, is that HAP mice will show increased sensitivity to the rewarding effects of alcohol, whereas LAP mice will not. Additional studies will determine whether free-choice alcohol consumption in HAP mice causes similar changes in behavior and neurochemistry. Overall, by increasing basic knowledge of neural, genetic, and behavioral mechanisms underlying excessive drinking, these studies may further development of drug-based treatments for alcoholism.